Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

doi:10.1073/pnas.0509313103

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33647

Edited by Joan Massagué, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved March 1, 2006 (received for review October 26, 2005)

Abstract

Non-small cell lung cancer (NSCLC) demonstrates a strong etiologic association with smoking. Although nicotine is not carcinogenic, it can induce cell proliferation and angiogenesis and suppress apoptosis induced by certain agents. Here we show that nicotine inhibits apoptosis induced by the drugs gemcitabine, cisplatin, and taxol, which are used to treat NSCLCs. This protection correlated with the induction of XIAP and survivin by nicotine in a panel of human NSCLC cell lines, and depletion of XIAP and survivin ablated the protective effects of nicotine. The antiapoptotic effects of nicotine were mediated by dihydro β-erythroidine-sensitive α3-containing nicotinic acetylcholine receptors and required the Akt pathway. Chromatin immunoprecipitation assays demonstrated that nicotine stimulation caused an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein (Rb) from survivin promoter in A549 cells. Moreover, ablation of E2F1 levels caused abrogation of the protective effects of nicotine against cisplatin-induced apoptosis in A549 cells whereas ablation of signal transducer and activator of transcription 3 levels had no effect. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that survivin and XIAP play a key role in the antiapoptotic activity of nicotine.

Footnotes

^†To whom correspondence should be addressed. E-mail: chellasp{at}moffitt.usf.edu
↵*Present address: Division of Anatomy and Cell Biology, Department of Cellular and Physiological Sciences, University of British Columbia, Room 313, 2177 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
Author contributions: S.C. designed research; P.D., R.K., B.J., and C.D. performed research; E.H. contributed new reagents/analytic tools; P.D. and S.C. analyzed data; and P.D. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

NSCLC,

non-small cell lung cancer;

IP,

immunoprecipitation;

siRNA,

small interfering RNA;

nAChR,

nicotinic acetylcholine receptor;

DhβE,

dihydro β-erythroidine;

Stat,

signal transducer and activator of transcription;

PARP,

poly(ADP-ribose)polymerase;

Rb,

retinoblastoma tumor suppressor protein.